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* Division of Oncology,
Hematology/Oncology Fellowship Training Program, and
Infectious Diseases Fellowship Training Program, Children’s Hospital of Philadelphia, Philadelphia PA, 19104;
Medical Scientist Training Program,
¶ Department of Pathology and Laboratory Medicine, and
|| Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia PA, 19104;
# Abramson Family Cancer Research Institute, Philadelphia, PA 19104; and
** Laboratory of Molecular Oncology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
The adaptor molecule SAP (signaling lymphocytic activation molecule-associated protein) plays a critical role during NK T (NKT) cell development in humans and mice. In CD4+ T cells, SAP interacts with the tyrosine kinase Fyn to deliver signals required for TCR-induced Th2-type cytokine production. To determine whether the SAP-dependent signals controlling NKT cell ontogeny rely on its binding to Fyn, we used the OP9-DL1 system to initiate structure function studies of SAP in murine NKT cell development. In cultures containing wild-type (WT) hematopoietic progenitors, we noted the transient emergence of cells that reacted with the NKT cell-specific agonist 
-galactosyl ceramide and its analog PBS57. Sap–/– cells failed to give rise to NKT cells in vitro; however, their development could be rescued by re-expression of WT SAP. Emergence of NKT cells was also restored by a mutant version of SAP (SAP R78A) that cannot bind to Fyn, but with less efficiency than WT SAP. This finding was accentuated in vivo in SapR78A knock-in mice as well as SapR78A competitive bone marrow chimeras, which retained NKT cells but at significantly reduced numbers compared with controls. Unlike SapR78A CD4+ T cells, which produce reduced levels of IL-4 following TCR ligation, -galactosyl ceramide-stimulated NKT cells from the livers and spleens of SapR78A mice produced Th2 cytokines and activated NK cells in a manner mimicking WT cells. Thus, SAP appears to use differential signaling mechanisms in NKT cells, with optimal ontogeny requiring Fyn binding, while functional responses occur independently of this interaction.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was funded by a grant from the National Institutes of Health (to K.E.N.).
2 Address correspondence and reprint requests to Dr. Kim E. Nichols, Children’s Hospital of Philadelphia, Wood Building Fourth Floor, Oncology Mailbox, 3615 Civic Center Boulevard, Philadelphia PA 19104. E-mail address: nicholsk{at}email.chop.edu
3 Abbreviations used in this paper: NKT, NK T cell; BM, bone marrow; DL1, Delta-like 1; DP, double positive; FL, fetal liver; -GC, -galactosyl ceramide; HSA, heat-stable Ag; SAP, signaling lymphocytic activation molecule-associated protein; SLAM, signaling lymphocytic activation molecule; Tet+, tetramer reactive; WT, wild type; XLP, X-linked lymphoproliferative disease.
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